1,2-Dichloroethane → HCID 68349533, compound

HRID 1507984Notes

Reaction equation

HRID 1507984 reaction equation
[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:19])[C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:22](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.N>C1COCC1>[NH2:22][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:19]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 222AmmoniaHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 68292087HCID 68292087, compound

Product 1

HCID 68349533HCID 68349533, compoundYield 53.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
25 °C

Procedure

To a solution of (R)-3-(((benzyloxy)carbonyl)amino)-2,2-dimethylbutanoic acid (9.0 g, 33.9 mmol) in THF (100 mL) under N2 atmosphere DIPEA (17.77 mL, 102 mmol) was added followed by addition of HOBT (5.19 g, 33.9 mmol) and EDC (6.50 g, 33.9 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h. Then freshly prepared saturated ammonia in THF 50 mL (50 mL of THF, ammonia gas was purged at −40° C. for 20 min) was poured into the above reaction mixture at −20° C. and slowly allowed reaction mass temperature to 25° C. and stirred for further 12 h. Upon completion of the reaction, it was quenched with water (250 mL) and extracted into ethyl acetate (2×200 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate, concentrated under reduced pressure to obtain pale brown oil. This crude product was purified by column chromatography using 60-120 silica gel, by eluted with ethyl acetate:hexane (40:60) to yield (R)-benzyl (4-amino-3,3-dimethyl-4-oxobutan-2-yl)carbamate (4.8 g, 46.5%) as pale yellow oil. 1HNMR (400 MHz, CDCl3) δ ppm: 7.36-7.35 (d, J=4.4 Hz, 5H), 5.104 (s, 2H), 3.75-3.67 (t, J=16, 18.4 Hz, 1H), 1.25-1.24 (d, J=5.2 Hz, 6H), 1.18-1.17 (d, J=6.8 Hz, 3H). HPLC purity: Column: Sunfire C18 (4.6×150 mm, 3.5 μm), Buffer: 0.05% TFA in H2O (pH 2.5, adjusted with ammonia), Solvent A: Buffer: CH3CN (95:5). Solvent B: Buffer: CH3CN (5:95). Time: 0-10, 12-100, 15-100 min, Flow: 1.0 mL/min Retention Time: 7.408: Purity: 93.74%. Chiral HPLC purity: Column: CHIRALPAK AD-H (250×4.6 mm) 5 micron, Mobile Phase: 0.2% DEA in hexane:ethanol (50:50). Flow: 1.0 mL/min: Retention Time: 6.036. Purity: 100%. LCMS Purity: Column: Ascentis C18 (5×2.1 mm-2.7 μm). Mobile Phase A: 2% ACN −98% H2O-10 mM NH4COOH. Mobile Phase B: 98% ACN −2% H2O-10 mM NH4COOH. Flow: 1.0 mL/min. Retention Time: 1.785 Min. Purity: 99.9% (m/z=265.2 M+).

Workup

  1. customslowly allowed reaction mass temperature to 25° C.
  2. stirringstirred for further 12 h
  3. customUpon completion of the reaction, it
  4. customwas quenched with water (250 mL)
  5. extractionextracted into ethyl acetate (2×200 mL)
  6. washThe combined organic layer was washed with brine solution
  7. dry with materialdried over anhydrous sodium sulphate
  8. concentrationconcentrated under reduced pressure
  9. customto obtain pale brown oil
  10. customThis crude product was purified by column chromatography
  11. washby eluted with ethyl acetate:hexane (40:60)

Sources & evidence

ORD record
ord-b9e2dbb37811472aa9647fa51bbf70df
Source dataset
uspto-grants-2015_12
Patent number
US09221826B2

Reaction notes

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